Decoding molecular mechanisms for loss-of-function variants in the human proteome

Abstract Proteins play a critical role in cellular function by interacting with other biomolecules; missense variants that cause loss of protein function can lead to a broad spectrum of genetic disorders. While much progress has been made on predicting which missense variants may cause disease, our ability to predict the underlying molecular mechanisms remain limited. One common mechanism is that missense variants cause protein destabilization resulting in decreased protein abundance and loss of function, while other variants directly disrupt key interactions with other molecules. We have here leveraged machine-learning models for protein sequence and structure to disentangle effects on protein function and abundance, and applied our resulting model to all missense variants in the human proteome. We find that approximately half of all missense variants that lead to loss of function and disease do so because they disrupt protein stability. We predicted functionally important positions in all human proteins and found that they cluster on protein structures and are often found on the protein surface. Our work provides a resource for interpreting both predicted and experimental variant effects across the human proteome, and a mechanistic starting point for developing therapies towards genetic diseases. Competing Interest Statement KL-L holds stock options in and is a consultant for Peptone Ltd. Footnotes Updates to how ESM-IF scores are calculated and to selection of variants from clinvar